The early stage of folding of villin headpiece subdomain observed in a 200-nanosecond fully solvated molecular dynamics simulation

Abstract

A new approach in implementing classical molecular dynamics simulation for parallel computers has enabled a simulation to be carried out on a protein with explicit representation of water an order of magnitude longer than previously reported and will soon enable such simulations to be carried into the microsecond time range. We have used this approach to study the folding of the villin headpiece subdomain, a 36-residue small protein consisting of three helices, from an unfolded structure to a molten globule state, which has a number of features of the native structure. The time development of the solvation free energy, the radius of gyration, and the mainchain rms difference from the native NMR structure showed that the process can be seen as a 60-nsec ''burst'' phase followed by a slow ''conformational readjustment'' phase. We found that the burial of the hydrophobic surface dominated the early phase of the folding process and appeared to be the primary driving force of the reduction in the radius of gyration in that phase.Understanding the mechanism of protein folding has been a grand challenge in protein chemistry for a few decades. Important advances in this area can have a profound impact in many biologically relevant fields. A direct benefit from the understanding of the mechanism should be the ability to predict protein structures more accurately, which in turn should enable the pharmaceutical industry to improve drug discovery. The recent hypothesis of folding-related diseases is another example of the significance of folding (1, 2). Despite great progress made by a variety of experimental and theoretical approaches, it has been difficult to establish detailed descriptions of the folding process and mechanism at an atomic level.Computer simulation has been a powerful tool that can provide rich information at various levels of resolution. Simulation has been instrumental in understanding protein folding mechanisms. One such approach is lattice model simulations (3-5). These types of models use reduced representations by treating the residues as (one or two) linked beads. A more detailed approach is the atomic level model, either unitedatom or all-atom, which represents all or most of the atoms of the protein explicitly, with an implicit representation of the solvent (6, 7). Molecular dynamics (MD) simulations with full atomic representation of both protein and solvent possess a unique advantage to study protein folding because of their atomic level resolution and accuracy. This method with associated simulation parameters (i.e., the force field) derived from experiments and from gas-phase quantum mechanical calculations has been tested by using smaller molecular systems in many comparisons with experimental results.Because of the complexity of this approach, the large number of atoms, and the need to take time steps of 1 to 2 fsec, such simulations have to date been limited to a few nanoseconds; the longest single MD trajectories of proteins with explicit water have been Ͻ10 nsec (8). This has pre...

Dynamic folding pathway models of the villin headpiece subdomain (HP‐36) structure

“…of native contacts (tertiary structure), with the correlation coefficient of 0.94. Thus, as far as the correlation between the formation of the secondary structures and the completion of the tertiary structure is concerned the present folding model is consistent with both computational 3,4 and experimental 43 results. The current study also agrees with the computational work by Duan et al, 3 where it is shown that the burst phase precedes the slow conformational readjustment phase in HP-36 folding.…”

“…[18][19][20][21] With a wellpacked hydrophobic core, HP-36 is thermodynamically stable under its folding condition. Because of its ultrafast folding rate and many mutation studies, HP-36 has served as a popular target for many folding studies both by theory 3,4,10,11,22 and experiment. [17][18][19][20][21]23 However, the nature of the HP-36 folding dynamics still remains to be clarified due to the lack of its microscopic information from experiments.…”

“…2 Computer simulation is a useful tool to study kinetic processes and thermodynamic stabilities of protein folding. [3][4][5][6][7][8][9][10][11][12] The most direct atomistic simulation technique is the conventional molecular dynamics (MD) method, 13 in which atomic motions are calculated by integrating the classical equations of motion for a given potential-energy function. Complementary to experiments, the MD simulation can provide time-dependent description of a protein system and, in principle, it can solve the protein folding problem.…”

Folding free-energy landscape of villin headpiece subdomain from molecular dynamics simulations

“…HP35 folding was first studied by a microsecond all-atom simulation (13,14) that did not reach the native state. Subsequently, Shen and Freed (15) performed a 200-ns simulation with an implicit solvent and also reached a semifolded state.…”

Classical Molecular Dynamics

“…However, the limits of such a demonstration became rather obvious, since for a usual production run of 10000 time steps a simulation time of a quarter of a year would be required (given that the whole machine is dedicated to one user). In another demonstration run Y. Duan and P. A. Kollman extended the time scale of an all atom MD simulation to 1 µs, where they simulated the folding process of the subdomain HP-36 from the villin headpiece 6,1 . The protein was modelled with a 596 interaction site model dissolved in a system of 3000 water molecules.…”